Abstract

Macrophages are critical for innate immune defense and also control organ homeostasis in a tissue-specific manner. They provide a fitting model to study the impact of ontogeny and microenvironment on chromatin state and whether chromatin modifications contribute to macrophage identity. Here, we profile the dynamics of four histone modifications across seven tissue-resident macrophage populations. We identify 12,743 macrophage-specific enhancers and establish that tissue-resident macrophages have distinct enhancer landscapes beyond what can be explained by developmental origin. Combining our enhancer catalog with gene expression profiles and open chromatin regions, we show that a combination of tissue- and lineage-specific transcription factors form the regulatory networks controlling chromatin specification in tissue-resident macrophages. The environment is capable of shaping the chromatin landscape of transplanted bone marrow precursors, and even differentiated macrophages can be reprogrammed when transferred into a new microenvironment. These results provide a comprehensive view of macrophage regulatory landscape and highlight the importance of the microenvironment, along with pioneer factors in orchestrating identity and plasticity.

Dataset information:

Genomic assay	Bulk RNA-seq	Samples	Microglia, Kupffer cells, spleen, lung, peritoneal, ileal, colonic MFs and monocytes
Method for deriving gene sets	K-means	Number of gene sets	11
Figure source	Figure 1	Data source	Table S1

Associated gene sets:

Gene set #	Description	No. of genes
1	Microglia	577
2	Kupffer cells & Spleen MΦ	287
3	Kupffer cells & Spleen & Lung MΦ	446
4	Lung MΦ	234
5	Lung & Peritoneal MΦ	177
6	Peritoneal MΦ	259
7	Ileal & Colonic MΦ	276
8	Monocytes	226
9	Shared	193
10	Shared	201
11	Shared	128

A total of 3004 genes are associated with this dataset.